The vanilloid receptor type 1 (VR1 or TRPV1) belongs to the wide family of transient receptor potential cationic channels (TRPV) with six trans-membrane domains. TRPV1 is the only TRPV channel that is presently known to be activated by some natural products, capsaicin and resiniferatoxin being the most known and studied (Sterner and Szallasi, Trends Pharmacol. Sci. 1999, 20, 459-465). Its is to date recognized that, while other TRPV channels, such as TRPV2, TRPV3 and TRPV4 (also known as “VR1-like (VRL) receptors”), are solely responsive to mechanical, osmotic or thermal stimuli and are in principle evenly distributed in the various tissues of mammals, TRPV1 specifically acts as a molecular integrator of pain stimulation induced, for instance, by heat, protons and vegetable toxins and is mainly expressed in peripheral sensory type C and Aδ fibres (Gunthorpe et al., Trends Pharmacol. Sci. 2002, 23, 183-191).
VR1-Knockout studies on transgenic mice univocally proved the role of TRPV1 in partial perception and transmission of “thermal” or “inflammatory” pain (Caterina et al., Science 2000, 288, 306-313; Davis et al., Nature 2000, 405, 183-187). Other studies suggested that TRPV1 is involved also in intestinal inflammatory disorders (Yiangou et al., Lancet 2001, 357, 1338-1339), neuropatic pain (Walker et al., J. Pharmacol. Exp. Ther. 2003, 304, 56-62), fecal incontinence and pathological cough (Chung and Chang, Pulm. Pharmacol. Ther. 2002, 15, 335-338). TRPV1 apparently plays a fundamental role also in the control of urinary bladder function (Birder et al., Nat. Neurosci. 2002, 5, 856-860) and in the control of neuronal plasticity, body temperature, food intake, energy expenditure, and movement (Di Marzo et al., Eur. J. Pharmacol. 2001, 420, 123-131).
Neurons expressing TPRV1 receptors can be desensitised immediately after activation by some agonists, such as capsaicin. From the practical point of view, the starting burning sensation due to the agonist action is overcome by a paradox effect. VR1 tachyphylaxis can also account for other medicinal effects described for capsaicin and chili pepper, such as the well-known anti-emetic and anti-inflammatory effects and the neuroprotective effect against glutamate excitotoxicity. Capsaicin and its analogue resiniferotoxin are also used in the treatment of urinary incontinence (wherein nerve ends characterized by the presence of VR participate in the transmission of the bladder emptying reflex), whereas capsaicin synthetic derivatives, the most known being olvanil, have been patented as oral analgesics. The pharmaceutical industry is, however, still remarkably interested in the development of more potent TRPV1 agonists.